tbuckley/cabot-search huggingface dataset:
Effect of tumor location on the efficacy of chemotherapy for gastrointestinal stromal tumors.
Authors: Ryan Sweeney, Shivani Shah, Rodney E. Wegner
Journal: Journal of Clinical Oncology (2023)

790 Background: Gastrointestinal stromal tumors (GISTs) arise from multiple sites within the gastrointestinal tract. Since the introduction of imatinib in 2002, patients have seen improved overall survival. However, a recent National Cancer Database (NCDB) study suggested no survival benefit to adjuvant imatinib for colorectal GIST patients. Another recent study showed that small bowel GISTs have larger median tumor size and higher incidence of tumors with at least 5 mitoses compared to gastric GISTs. These findings suggest a differential tumor biology for GISTs arising from different primary tumor sites, potentially conferring differential response to imatinib. In this NCDB study, we compare overall survival outcomes with and without chemotherapy, stratifying by primary tumor site. Methods: We queried the NCDB from 2004-2018 for patients with GIST histology. We excluded patients with age &lt;40, age&gt;80, high comorbidity score, and patients who received additional therapy other than surgery or chemotherapy. Of the 22,846 patients meeting criteria for our study, 27 patients had tumors originating from the anus, 454 from the colon, 173 from the esophagus, 15,296 from the stomach, 556 from the rectum, 32 from the rectosigmoid junction, and 6,308 from the small intestine. 8,983 (39%) received chemotherapy. Treatment with chemotherapy was used to extrapolate response to imatinib, the mainstay of treatment. Results: Cox proportional hazards analysis demonstrated increased hazard of death for chemotherapy, increasing age, and comorbidity score of 1. Positive predictive factors for survival included female sex and later year of diagnosis. For anal, esophageal, gastric, and rectosigmoid GIST patients, there was no statistically significant overall survival benefit for any treatment modality. For colonic GISTs, neoadjuvant chemotherapy combined with surgery improved overall survival. For rectal GISTs, adjuvant chemotherapy with surgery also provided survival benefit. For small intestinal GISTs, surgery alone or surgery with neoadjuvant, adjuvant, or both neoadjuvant and adjuvant chemotherapy improved overall survival. Conclusions: While our study is retrospective and limited as a NCDB study, our Kaplan-Meier survival analysis demonstrated survival benefit for chemotherapy only in patients with colon, rectal, or small intestinal GIST tumors. Our Cox proportional analysis demonstrated an overall negative survival impact for chemotherapy. These findings lend further support to the idea that differential tumor biology at each primary site may lead to differential response to imatinib. Overall, our study provides rationale for further investigating the heterogeneity of GIST tumor microenvironments, as these differences could contribute to the differential treatment outcomes.
Use of glycoproteome profiles to detect advanced adenomas and colorectal cancer.
Authors: Khushbu Desai, Alan Mitchell, Ankita Shah, Dharini Chandrasekar, Gege Xu, Klaus Lindpaintner, Dan Serie, Tillman E. Pearce, Daniel Hommes
Journal: Journal of Clinical Oncology (2023)

69 Background: Colorectal cancer (CRC) remains a leading cancer despite current screening modalities. Precancerous lesions, or Advanced Adenomas (AA), commonly precede invasive cancer development by years. Newer technologies use circulating tumor DNA and/or proteins for CRC detection but have not been able to effectively detect AA. Aberrant protein glycosylation is associated with (pre-)malignant lesions. To detect glycoproteome profiles associated with the occurrence of AA, we studied serum glycoproteins in AA/CRC. Methods: A novel platform combining liquid-chromatography/mass-spectrometry (LC-MS) and artificial-intelligence (AI)-powered data processing allowing high resolution, high throughput glycoproteomic profiling was used to identify glycoprotein biomarkers in peripheral blood. Samples were sourced from biorepositories and included patients diagnosed with CRC, AA, ulcerative colitis (UC) and controls. The samples were split into a training (50%) and a hold-out testing set (50%) for the development of a machine learning (ML)-based multivariable predictive model. Statistical analysis was performed on normalized data to identify biomarkers differentiating AAs and different stages of CRC from controls. Results: We studied 563 patient samples: 196 controls (mean age 51.7; 52% female); 32 AA (mean age 68.6; 53% female); 247 CRC (mean age 65.6; 50% female) and 88 UC (mean age 44.1; 47% female). There were 250 differentially abundant (FDR &lt; 0.05) glycopeptides/peptides when comparing CRC and AA samples with healthy and UC controls. A subset was assessed, generating a six (6) biomarker ML classification model. This model was applied to the hold-out test and achieved an overall sensitivity of 91.4% and specificity of 91.8% for predicting AA/CRC versus healthy/UC with an area under the receiver operating characteristic of 0.962. AA and CRC separately were predicted with a sensitivity of 84.4% and 92.8%, respectively, relative to healthy/UC with sensitivities for CRC stage 1/2 and stage 3/4 being 91.2% and 93.2%, respectively). Conclusions: Glycoproteomic serum profiles accurately detect precancerous AA in addition to CRC and offer a new approach to effective CRC screening. We will have completed an interim analysis of a large prospective observational study at the time of the meeting. Clinical trial information: NCT05445570 . [Table: see text]
Sidedness and addition of chemotherapy associated with treatment outcomes of regorafenib for metastatic colorectal cancer (mCRC).
Authors: Tsung-Che Wu, Yi-Hsin Liang, Kuo-Hsing Chen, Chien Huai Chuang, Yu Yun Shao
Journal: Journal of Clinical Oncology (2023)

36 Background: Regorafenib is one of the options of salvage treatment for mCRC. We aimed to explore the prognostic factors of such regorafenib treatment. Methods: We searched the database of National Health Insurance, Taiwan for patients who initiated regorafenib treatment for mCRC from September 1, 2015, to December 31, 2018. Database interrogation of National Death Registry, Taiwan and Taiwan Cancer Registry was conducted for survival data and clinicopathological variables, respectively. Results: A total of 3,643 patients were included in the analysis. The median age was 61.2 years. The primary tumor was left-sided and KRAS mutant in 75.3% and 54.5% of patients, respectively; 28.9% of patients received chemotherapy simultaneously, with irinotecan as the most common companion. The median time to treatment discontinuation (TTD) was 2.3 months (95% confidence interval [CI]: 95% CI: 2.3-2.3), and the median overall survival (OS) was 7.2 months (95% CI: 6.9-7.4). Patients with left-sided primary tumors, compared with patients with right-sided tumors, exhibited significantly longer TTD (median, 2.4 vs. 2.1 months, p &lt; 0.001) and OS (median, 7.6 vs. 6.1 months, p &lt; 0.001). By contrast, TTD and OS of patients under regorafenib treatment were similar regardless the KRAS mutation status ( p = 0.415 and 0.643, respectively). Patients who received chemotherapy along with regorafenib, compared with patients who did not, also exhibited significantly longer TTD (median, 2.6 vs. 2.2 months, p &lt; 0.001) and OS (median, 8.3 vs. 6.7 months, p &lt; 0.001). In multivariate analysis adjusting age, sex, time from colorectal cancer diagnosis, hospital level, KRAS mutation, and initial regorafenib dose, left-sidedness of the primary tumor remained a predictor for better TTD (hazard ratio [HR]: 0.88, p = 0.002) and OS (HR: 0.92, p = 0.048), as well as addition of chemotherapy (for TTD, HR: 0.86, p &lt; 0.001; for OS, HR: 0.76, p &lt; 0.001). Due to the interaction between sidedness and KRAS mutation, we established separate Cox models and found that left-sided primary tumor was an independent predictor for better TTD and OS for KRAS wild-type tumors, but not for KRAS mutant tumors. Conclusions: In this population-wide cohort study, left-sided primary tumor and addition of chemotherapy were associated with better TTD and OS of regorafenib treatment for mCRC.
Comparison of clinical features by primary sites in patients with biliary tract cancer who received gemcitabine-based chemotherapy: An exploratory analysis of JCOG1113.
Authors: Yuko Suzuki, Chigusa Morizane, Junki Mizusawa, Yusuke Sano, Satoshi Kobayashi, Hiroshi Imaoka, Takeshi Terashima, Masafumi Ikeda, Naohiro Okano, Kazuya Sugimori, Akiko Todaka, Satoshi Shimizu, Nobumasa Mizuno, Mitsugu Sekimoto, Keiji Sano, Kazutoshi Tobimatsu, Akio Katanuma, Takuji Okusaka, Masato Ozaka, Makoto Ueno
Journal: Journal of Clinical Oncology (2023)

548 Background: Biliary tract cancers (BTCs) include gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (IHCC), extrahepatic cholangiocarcinoma (EHCC), and ampulla of Vater cancer (AV). Although it was previously reported that there were differences in clinical features individually, the reported data were limited to data from some subgroup analyses of recent randomized controlled trials. JCOG1113 (UMIN000010667) showed the non-inferiority of gemcitabine plus S-1 to gemcitabine plus cisplatin in terms of overall survival (OS) in patients (pts) with advanced BTCs. We aimed to compare clinical features among the primary sites of BTCs using JCOG1113 data. Methods: Among the 354 pts enrolled in JCOG1113, 352 pts were included in this analysis except for 2 pts without BTCs. We compared the patient characteristics and treatment outcomes, such as OS, progression-free survival (PFS), and objective response rate (ORR), among the four primary sites. Results: Of the 352 pts, 137 pts (38.9%), 94 pts (26.7%), 108 pts (30.7%) and 13 pts (3.7%) had GBC, IHCC, EHCC, and AV, respectively. GBC was more common in females (58.4%) than males, in contrast to the other primary sites. The percentage of pts with metastatic disease for GBC was the highest (78.1%) and involved multiple metastatic organs (41.6%), in contrast with the other primary sites. The median OS for GBC, IHCC, EHCC and AV were 12.6 months (reference), 15.7 months (hazard ratio [HR]; 0.749, 95% confidence interval [CI], 0.559-1.005), 16.3 months (0.704, 0.532-0.934) and 11.5 months (1.148, 0.633-2.080), respectively. The median PFS for GBC, IHCC, EHCC and AV were 5.7 months (reference), 6.2 months (0.843, 0.644-1.104), 8.7 months (0.636, 0.489-0.826) and 4.1 months (1.506, 0.851-2.665), respectively. The ORRs for GBC, IHCC, EHCC and AV were 34.4%, 28.9%, 34.4%, and 0.0%, respectively. Conclusions: Except for AV which included a few patients in this trial, GBC showed a poorer prognosis compared with the other primary sites. Furthermore, it was more likely to include metastatic disease and multiple metastases, and this is likely one of the causes of the poorer prognosis. [Table: see text]
HER2 testing in colorectal cancer: Concordance analysis between breast and gastric scoring algorithms from the MOUNTAINEER trial.
Authors: Andrea Cercek, Kimmie Ng, John H Strickler, Salvatore Siena, Thierry Andre, Eric Van Cutsem, Christina Wu, Andrew Scott Paulson, Joleen M. Hubbard, Andrew L. Coveler, Christos Fountzilas, Adel Kardosh, Pashtoon Murtaza Kasi, Heinz-Josef Lenz, Kristen Keon Ciombor, Elena Elez, Michael Stecher, Pauline Cronin, Wentao Feng, Tanios S. Bekaii-Saab
Journal: Journal of Clinical Oncology (2023)

198 Background: HER2 overexpression/amplification (HER2+) occurs in 3%-5% of patients (pts) w/ metastatic colorectal cancer (mCRC). Rates of HER2+ can increase to ~10% in pts w/ RAS/BRAF wild-type mCRC tumors. The MOUNTAINEER trial (NCT03043313) evaluated the efficacy and safety of the investigational combination of tucatinib with trastuzumab in pts with HER2+ and RAS wild-type mCRC. Established regional guidelines for mCRC recommend HER2 testing and HER2-directed treatment options; however, there is currently no established best practice for HER2 testing and interpretation in mCRC. Here, we present data from a concordance analysis comparing breast and gastric HER2 testing algorithms in the mCRC setting. Methods: The MOUNTAINEER trial enrolled pts w/ HER2+ mCRC identified using ≥1 method: tissue-based local immunohistochemistry (IHC), in situ hybridization (ISH), and/or next-generation sequencing (NGS) testing. Archival or fresh tumor tissue was submitted to a sponsor-designated central laboratory for confirmatory HER2 testing w/ IHC/FISH per the package insert of the FDA approved assay and scored by both the breast and gastric algorithms for HER2 IHC. A positive result per the breast scoring criteria for IHC requires circumferential membrane staining for HER2, while the gastric criteria allows for circumferential, basolateral, or lateral staining patterns. Results: A total of 114 pts were enrolled with HER2+ tumors per ≥1 local testing methods; 69 pts were HER2+ by NGS, 46 by IHC 3+, and 36 by ISH. Of 105 pts who had tissue available for central HER2 testing w/IHC/FISH, 98 had valid HER2 results; 82/98 (83.7%) of pts had tumors centrally confirmed as HER2+ using both the breast and gastric algorithms. Tissue samples from pts in the MOUNTAINEER trial had 100% concordance between breast and gastric algorithms in HER2 status and 99% concordance in HER2 IHC score. Conclusions: Central pathology testing using both the breast and gastric criteria showed high concordance between these two commonly used algorithms. A high central confirmation rate of local HER2+ results was also observed. These data support the use of either the breast or gastric algorithms to identify HER2+ mCRC tumors until an FDA-approved HER2 assay is available for mCRC. Clinical trial information: NCT03043313 . [Table: see text]
A double-blind, randomized, placebo-controlled, parallel study to investigate the auxiliary effects of fucoidan in patients with locally advanced rectal cancer who receive neoadjuvant concurrent chemoradiotherapy before surgery.
Authors: Jaw-Yuan Wang, Hsiang-Lin Tsai
Journal: Journal of Clinical Oncology (2023)

12 Background: Preoperative concurrent chemoradiotherapy (CCRT) is the standard treatment for patients with locally advanced rectal cancer (LARC). Low molecular weight fucoidan (LMF) is widely used as food supplements in cancer patients. This study is aimed to evaluate the efficacy of LMF as supplemental therapy to CCRT in LARC patients. Methods: We conducted a double-blind, prospective, randomized, placeo-controlled study to investigate the auxiliary effects of fucoidan in 107 patients with LARC who receive neoadjuvant CCRT before surgery. Finally, 87 patients were enrolled, of whom 44 were included in the study (fucodin) group and 43 in the control (placebo) group. The primary endpoint was the EORTC QLQ-C30 and FACT-C quality of life (QoL), and secondary endpoints included the overall response rate (ORR), disease control rate (DCR) and adverse events (AEs). Results: The physical well-being (PWB) was much improved after 2-month administration in the study (fucodin) group when compared with placebo group ( P= 0.007), whereas colorectal cancer subscale (CCS) was also better after 3-month administration when compared with placebo group ( P= 0.034). ORR and DCR were not significantly different between 2 groups (both P &gt; 0.05). Moreover, skin rash ( P= 0.038) and fatigue ( P= 0.008) was less common in the fucodin group. Conclusions: This is the first clinical trial evaluating the efficacy of LMF as a supplemental therapy in the management of patients with LARC who undergoing CCRT. The results indicate that LMF would significantly improve QoL and decrease AEs of skin rash/fatigue; however, a long-term follow up is mandatory for the confirmation of oncological outcomes by LMF. Clinical trial information: NCT04342949 .
Spatiotemporal Metabolic Liver Zonation and Consequences on Pathophysiology
Authors: Tomaz Martini, Felix Naef, Jan S. Tchorz
Journal: Annual Review of Pathology Mechanisms of Disease (2023)

Hepatocytes are the main workers in the hepatic factory, managing metabolism of nutrients and xenobiotics, production and recycling of proteins, and glucose and lipid homeostasis. Division of labor between hepatocytes is critical to coordinate complex complementary or opposing multistep processes, similar to distributed tasks at an assembly line. This so-called metabolic zonation has both spatial and temporal components. Spatial distribution of metabolic function in hepatocytes of different lobular zones is necessary to perform complex sequential multistep metabolic processes and to assign metabolic tasks to the right environment. Moreover, temporal control of metabolic processes is critical to align required metabolic processes to the feeding and fasting cycles. Disruption of this complex spatiotemporal hepatic organization impairs key metabolic processes with both local and systemic consequences. Many metabolic diseases, such as nonalcoholic steatohepatitis and diabetes, are associated with impaired metabolic liver zonation. Recent technological advances shed new light on the spatiotemporal gene expression networks controlling liver function and how their deregulation may be involved in a large variety of diseases. We summarize the current knowledge about spatiotemporal metabolic liver zonation and consequences on liver pathobiology.
Pathogenic Variants in Adult-Onset Cancer Predisposition Genes in Pediatric Cancer: Prevalence and Impact on Tumor Molecular Features and Clinical Management
Authors: Rose B. McGee, Ninad Oak, Lynn Harrison, Ke Xu, Regina Nuccio, Alise K. Blake, Roya Mostafavi, Sara Lewis, Leslie M. Taylor, Manish Kubal, Annastasia Ouma, Stacy J. Hines-Dowell, Cheng Cheng, Larissa V. Furtado, Kim E. Nichols
Journal: Clinical Cancer Research (2023)

Clinical genomic sequencing of pediatric tumors is increasingly uncovering pathogenic variants in adult-onset cancer predisposition genes (aoCPG). Nevertheless, it remains poorly understood how often aoCPG variants are of germline origin and whether they influence tumor molecular profiles and/or clinical care. In this study, we examined the prevalence, spectrum, and impacts of aoCPG variants on tumor genomic features and patient management at our institution.This is a retrospective study of 1,018 children with cancer who underwent clinical genomic sequencing of their tumors. Tumor genomic data were queried for pathogenic variants affecting 24 preselected aoCPGs. Available tumor whole-genome sequencing (WGS) data were evaluated for second hit mutations, loss of heterozygosity (LOH), DNA mutational signatures, and homologous recombination deficiency (HRD). Patients whose tumors harbored one or more pathogenic aoCPG variants underwent subsequent germline testing based on hereditary cancer evaluation and family or provider preference.Thirty-three patients (3%) had tumors harboring pathogenic variants affecting one or more aoCPGs. Among 21 tumors with sufficient WGS sequencing data, six (29%) harbored a second hit or LOH affecting the remaining aoCPG allele with four of these six tumors (67%) also exhibiting a DNA mutational signature consistent with the altered aoCPG. Two additional tumors demonstrated HRD, of uncertain relation to the identified aoCPG variant. Twenty-one of 26 patients (81%) completing germline testing were positive for the aoCPG variant in the germline. All germline-positive patients were counseled regarding future cancer risks, surveillance, and risk-reducing measures. No patients had immediate cancer therapy changed due to aoCPG data.AoCPG variants are rare in pediatric tumors; however, many originate in the germline. Almost one third of tumor aoCPG variants examined exhibited a second hit and/or conferred an abnormal DNA mutational profile suggesting a role in tumor formation. aoCPG information aids in cancer risk prediction but is not commonly used to alter the treatment of pediatric cancers.
Genomic Complexity Predicts Resistance to Endocrine Therapy and CDK4/6 Inhibition in Hormone Receptor–Positive (HR+)/HER2-Negative Metastatic Breast Cancer
Authors: Andrew A. Davis, Jingqin Luo, Tiantian Zheng, Chao Dai, Xiaoxi Dong, Lu Tan, Rama Suresh, Foluso O. Ademuyiwa, Caron Rigden, Timothy P. Rearden, Katherine Clifton, Katherine Weilbaecher, Ashley Frith, Pavan K. Tandra, Tracy Summa, Brittney Haas, Shana Thomas, Leonel F. Hernandez-Aya, Lindsay L. Peterson, Xiaohong Wang, Shujun J. Luo, Kemin Zhou, Pan Du, Shidong Jia, Bonnie L. King, Jairam Krishnamurthy, Cynthia X. Ma
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Clinical biomarkers to identify patients unlikely to benefit from CDK4/6 inhibition (CDK4/6i) in combination with endocrine therapy (ET) are lacking. We implemented a comprehensive circulating tumor DNA (ctDNA) analysis to identify genomic features for predicting and monitoring treatment resistance. Experimental Design: ctDNA was isolated from 216 plasma samples collected from 51 patients with hormone receptor–positive (HR+)/HER2-negative (HER2−) metastatic breast cancer (MBC) on a phase II trial of palbociclib combined with letrozole or fulvestrant (NCT03007979). Boosted whole-exome sequencing (WES) was performed at baseline and clinical progression to evaluate genomic alterations, mutational signatures, and blood tumor mutational burden (bTMB). Low-pass whole-genome sequencing was performed at baseline and serial timepoints to assess blood copy-number burden (bCNB). Results: High bTMB and bCNB were associated with lack of clinical benefit and significantly shorter progression-free survival (PFS) compared with patients with low bTMB or low bCNB (all P &amp;lt; 0.05). Dominant APOBEC signatures were detected at baseline exclusively in cases with high bTMB (5/13, 38.5%) versus low bTMB (0/37, 0%; P = 0.0006). Alterations in ESR1 were enriched in samples with high bTMB (P = 0.0005). There was a high correlation between bTMB determined by WES and bTMB determined using a 600-gene panel (R = 0.98). During serial monitoring, an increase in bCNB score preceded radiographic progression in 12 of 18 (66.7%) patients. Conclusions: Genomic complexity detected by noninvasive profiling of bTMB and bCNB predicted poor outcomes in patients treated with ET and CDK4/6i and identified early disease progression before imaging. Novel treatment strategies including immunotherapy-based combinations should be investigated in this population.
Oropharyngeal Carcinoma with a Special Focus on HPV-Related Squamous Cell Carcinoma
Authors: Robert L. Ferris, William Westra
Journal: Annual Review of Pathology Mechanisms of Disease (2023)

Human papillomavirus–positive oropharyngeal squamous cell carcinoma (HPV-OPSCC) has one of the most rapidly increasing incidences of any cancer in high-income countries. The most recent (8th) edition of the Union for International Cancer Control/American Joint Committee on Cancer staging system separates HPV-OPSCC from its HPV-negative counterpart to account for the improved prognosis seen in the former. Indeed, owing to its improved prognosis and greater prevalence in younger individuals, numerous ongoing trials are examining the potential for treatment deintensification as a means to improve quality of life while maintaining acceptable survival outcomes. Owing to the distinct biology of HPV-OPSCCs, targeted therapies and immunotherapies have become an area of particular interest. Importantly, OPSCC is often detected at an advanced stage, highlighting the need for diagnostic biomarkers to aid in earlier detection. In this review, we highlight important advances in the epidemiology, pathology, diagnosis, and clinical management of HPV-OPSCC and underscore the need for a progressive understanding of the molecular basis of this disease toward early detection and precision care.